THE DEVELOPMENT OF THERAPEUTIC MONOCLONAL ANTIBODY PRODUCTS
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Excerpt of Chapter 13

Manufacturing strategy decisions involve significant capital as well as the opportunity cost of allocating funds away from other important initiatives. Building an in-house manufacturing facility could take five years or more and cost in excess of $250 million, while there is no guarantee that an outsourced solution will be available when needed, or sufficiently cost effective and flexible to meet the needs of the company. The technological risks associated with drug development efforts are high, and the probability of a monoclonal antibody in pre-clinical development successfully reaching the market is less than 20%.... To mitigate uncertainty, different approaches to manufacturing strategy can be pursued, depending on the strategic drivers deemed most important to the organization. Two idealized strategic approaches can be envisioned to balance pipeline demand with capacity supply. Figure 13.2 shows an example of a make (or build) strategy adopted early in the product life cycle when risk and uncertainty are greatest, and maximum control of operations is the driving force for the company… New business and clinical developments can lead companies without a well-developed strategy to unduly sway the manufacturing strategy to either end of the make versus buy spectrum. A manufacturing strategy value proposition should be formed to guide the strategic planning process and to minimize these fluctuations. This proposition would describe the current and future state of a company’s manufacturing capabilities including access to proprietary knowledge and/or technology, ability to innovate, operational excellence, risk management and the ability to add value to the organization. The timing, costs and benefits of achieving this future state should be included….

Figure 13.2.  Maximizing Control of Manufacturing during Early Stage Development

There are several essential elements to successful negotiations with CMOs. It is important to understand the CMO's business model and motivations during negotiations. Fundamentally, the CMO is providing infrastructure and capacity such as access to a GMP facility, trained operators, and GMP quality systems and procedures. When negotiating the business terms, the key is to tie pay to performance. Focus on the specific tasks to be performed, for what cost and for what deliverables. Keep in mind that a service is being purchased, not an “off-the-shelf” product. A good and fair contract will have appropriately allocated risk between the parties. The contract should detail mutual responsibilities (the who, what, where, when, and how), standards for performance, procedures to remedy faulty performance, intellectual property ownership and rights to use, regulatory compliance, and warranties and indemnification as well as quality obligations, generally found as an attachment in a quality agreement…

The role of a pilot plant in development and manufacturing is to enable process development at a scale closer to commercial scale, using equipment and unit operations that more closely simulate the larger scale equipment and to provide material for clinical trials as quickly and safely as possible. Occasionally, a pilot plant will also be used as a market launch facility for a new product. A simple monoclonal antibody pilot plant consists of an upstream cell culture train with a single downstream purification train. The pilot plant will often include small, manual filling operations for single lot hand fills up to about 2,000 vials. Alternatively, drug product manufacturing can be outsourced to a CMO offering aseptic fill capability.

Having the pilot plant site situated close to the groups responsible for product development will often help facilitate continued process development, technology transfers, and rapid production of clinical material. The pilot plant will be used to manufacture many different products over a number of years. During this time, technologies will change and as will process definition parameters (e.g., final product titer in cell culture harvest). These challenges can best be met by having a flexible facility design that can handle multi-products and that has the proper equipment…. Single-use technologies have gained varying degrees of acceptance in several applications as a means of increasing operational flexibility and reducing up-front capital costs. Applications of single-use systems can be found at most stages of processing, including the inoculum seed train, production bioreactors, media and buffer preparation, in-process intermediate hold and transfer steps, and purification. Single-use technologies simplify product change over and cleaning requirements.

For a facility designed around the use of single-use systems, the facility layout can simplify material and personnel flows, reduce the amount of equipment pieces, and equipment and utility requirements. Single-use components eliminate the requirement for extensive process piping that runs to and from process equipment. Media, buffer, and product transfers are made by connecting flexible tubes with tubing welders or quick connects, and piping for SIP and CIP operations can be eliminated.

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